Regulation of cancer and aging by FoxO and investigation of compounds for regulation of FoxO

• Project/Area Number: 15H04682
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental physiology(including physical medicine and nutritional physiology)
• Research Institution: Nagasaki University
• Principal Investigator: SHIMOKAWA Isao 長崎大学, 医歯薬学総合研究科(医学系), 教授 (70187475)
• Co-Investigator(Kenkyū-buntansha): 森 亮一 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (30509310) ; 朴 盛浚 長崎大学, 医歯薬学総合研究科(医学系), 助教 (60635853)
• Research Collaborator: KOMATSU Toshimitsu
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 老化 / カロリー制限 / FoxO転写因子 / 癌 / フォークヘッド転写因子 / カロリー制限模倣剤 / 発達・成長・老化 / ミトコンドリア

Outline of Final Research Achievements

To elucidate the differential roles of FoxO1 and 3 in inhibition of cancer and extension of lifespan by calorie restriction (CR), we focused on mitochondria functions and metabolism in Foxo1+/- and Foxo3+/- mice. Oxygen consumption rates in the state 3 of mitochondria isolated from liver tissues were greater in Foxo3+/- CR mice than in WT CR mice at 24 months of age (mo). The mitochondrial membrane potential was also elevated in Foxo3+/- CR mice. A hepatic metabolome revealed that some metabolites in the glycolysis were significantly affected in Foxo3+/- CR mice. These findings suggest necessity of FoxO3 for inhibition by CR of aging-related declines in mitochondrial functions and metabolism. A carcinogen-induced hepatocellular carcinoma model suggests that FoxO3 is required for development of the tumor. Conditional knock-out of Foxo3 gene in the white adipose tissue and in the brain indicated that these tissues are not essential for the life-extending effect of CR.

Academic Significance and Societal Importance of the Research Achievements

ヒトのFOXO3遺伝子多形と長寿の関連性が複数の集団で指摘されていた。CRによる寿命延伸に関わるFoxO3関連メカニズムを解明することは、ヒトの健康寿命の延伸メカニズムに迫ることができる点で、学術的、社会的意義は大きい。今後、アイソフォーム特異的活性化化合物を探索できれば、老化関連疾患の制御を目指す創薬に発展できる。

Research Products

• [Int'l Joint Research] Pusan National University(韓国)
• [Int'l Joint Research] Korean Society of Gerontology/Pusan National University(韓国)
• [Int'l Joint Research] National Yang Ming University(Taiwan)
• [Int'l Joint Research] The University of Hongkong(Hongkong)
• [Int'l Joint Research] Pusan National University(韓国)
• [Journal Article] NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning (2018)
  • Author(s): Park S, Nayantai E, Komatsu T, Hayashi H, Mori R, Shimokawa I.
  • Journal Title: J Gerontol A Biol Sci Med Sci Volume: - Issue: 6 Pages: 1042-1049
  • DOI: 10.1093/gerona/gly282
  • NAID: 120006988174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 基礎老化研究の展望：基礎老化学会が果たす役割 (2018)
  • Author(s): 下川 功
  • Journal Title: 老年医学 Volume: 上 Pages: 51-56
• [Journal Article] Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway (2017)
  • Author(s): Jenwitheesuk A, Park S, Wongchitrat P, Tocharus J, Mukda S, Shimokawa I, Govitrapong P
  • Journal Title: Neurochem Res Volume: 43 Issue: 1 Pages: 144-152
  • DOI: 10.1007/s11064-017-2369-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuropeptide Y resists excess loss of fat by lipolysis in calorie-restricted mice: A trait potential for the life-extending effect of calorie restriction (2017)
  • Author(s): Park S, Komatsu T, Kim SE, Tanaka K, Hayashi H, Mori R, Shimokawa I
  • Journal Title: Aging Cell Volume: 16 Issue: 2 Pages: 339-348
  • DOI: 10.1111/acel.12558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FoxO1 signaling plays a pivotal role in the cardiac telomere biology responses to calorie restriction. (2016)
  • Author(s): Makino N, Oyama J, Maeda T, Koyanagi M, Higuchi Y, Shimokawa I, Mori N, Furuyama T.
  • Journal Title: Mol Cell Biochem. Volume: 412 Issue: 1-2 Pages: 119-130
  • DOI: 10.1007/s11010-015-2615-8
  • Peer Reviewed / Open Access
• [Journal Article] The life-extending effect of dietary restriction requires Foxo3 in mice (2015)
  • Author(s): Shimokawa I, Komatsu T, Hayashi N, Kim SE, Kawata T, Park S, Hayashi H, Yamaza H, Chiba T, Mori R
  • Journal Title: Aging Cell Volume: - Issue: 4 Pages: 707-707
  • DOI: 10.1111/acel.12340
  • Peer Reviewed / Open Access
• [Presentation] Roles for FoxO transcription factors in the anti-aging effect of dietary restriction (2018)
  • Author(s): Shimokawa I
  • Organizer: The 12th International Symposium for Aging (2-3 November, 2018, Gwangju, Korea)
  • Int'l Joint Research / Invited
• [Presentation] カロリー制限による老化制御機構 (2018)
  • Author(s): 下川 功
  • Organizer: 第２９回 フォーラム・イン・ドージン、2018年11月22日、熊本
  • Invited
• [Presentation] ほ乳類の老化制御機構 (2018)
  • Author(s): 下川 功
  • Organizer: 第70回西日本泌尿器科学会総会、2018年11月2日、長崎
  • Invited
• [Presentation] Differential roles for FoxO1 and FoxO3 in regulation of cancer and lifespan in dietary-restricted mice (2017)
  • Author(s): Shimokawa I
  • Organizer: The 21st IAGG World Congress of Gerontology and Geriatrics
  • Int'l Joint Research
• [Presentation] Anti-Ageing Effect of Dietary Restriction (2016)
  • Author(s): Shimokawa I
  • Organizer: Biomembrane 2016: Mechanisms of aging and age-related diseases
  • Place of Presentation: Moscow, Rossia
  • Year and Date: 2016-09-26
  • Int'l Joint Research / Invited
• [Presentation] Distinct roles of Foxo1 and Foxo3 in the anti-neoplastic and the life-extending effects of dietary restriction-Implication of Foxo3 in regulation of mitochondrial integrity during the aging process (2015)
  • Author(s): Shimokawa I
  • Organizer: The 2015 Cold Spring Harbor Asia Conference
  • Place of Presentation: Suzhou, China
  • Year and Date: 2015-09-14
  • Int'l Joint Research / Invited
• [Book] Hormones in Ageing and Longevity, Healthy Ageing and Longevity 6 (2017)
  • Author(s): Shimokawa I
  • Total Pages: 16
  • Publisher: Springer International Publishing AG
• [Book] HORMONES IN AGEING AND LONGEVITY (2017)
  • Author(s): Shimokawa I (eds. Rattan SIS and Sharma R
  • Total Pages: 10
  • Publisher: Springer
• [Remarks] 長崎大学大学院医歯薬学総合研究科医療科学専攻病理学分野
  • URL: http://www.med.nagasaki-u.ac.jp/pathlgy1/
• [Remarks] 探索病理学
  • URL: http://www.med.nagasaki-u.ac.jp/pathlgy1/index/index.htm